Eissner, Guenther and Multhoff, Gabriele and Gerbitz, Armin and Kirchner, Silvia and Bauer, Sonja and Haffner, Silvia and Sondermann, Daniela and Andreesen, Reinhard and Holler, Ernst (2002) Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. BLOOD, 100 (1). pp. 334-340. ISSN 0006-4971
Full text not available from this repository. (Request a copy)Abstract
Fludarabine is a nonmyeloablative immunosuppressant increasingly used as a component of alternative conditioning regimens before allogeneic bone marrow transplantation. It is expected to reduce conditioning-related toxicity and proinflammatory activation of the host tissues. However, in our in vitro study, we provide evidence that 2-fluoroadenine 9-p-beta-arabinofuranoside (F-Ara) as the active metabolized form of fludarabine damages human microvascular endothelial cells (HMECs) and dermal and alveolar epithelial cell lines after 48 hours of culture when it is used in pharmacologically relevant concentrations (range, 10 mug/mL-1 mug/mL). In addition, flow cytometric analyses revealed a significant up-regulation of intercellular adhesion molecule 1 and major histocompatibility complex (MHC) class I molecules by F-Ara, suggesting a proinflammatory activation of HMECs. Cytotoxicity assays demonstrated that target HMECs pretreated with F-Ara (10 mug/mL) showed increased lysis by allogeneic MHC class I-restricted cytotoxic T lymphocytes from healthy human donors. We conclude that, beside its immunosuppressive activities, F-Ara can be harmful for target tissues of transplantation-related complications and can even stimulate allogeneic immune responses. We identified the pharmaceutical compound defibrotide as protective against F-Ara-induced apoptosis and alloactivation, importantly, without affecting the antileukemic effect of F-Ara. This observation argues for a potential clinical usage of defibrotide in pretransplantation conditioning.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BONE-MARROW TRANSPLANTATION; VERSUS-HOST DISEASE; RADIATION-INDUCED ACTIVATION; NECROSIS-FACTOR-ALPHA; BACTERIAL-ENDOTOXIN; IN-VITRO; VENOOCCLUSIVE DISEASE; T-LYMPHOCYTES; DEATH; VIVO; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Oct 2021 10:50 |
| Last Modified: | 18 Oct 2021 10:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/40100 |
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